EP4117658A1 - Substituted isoxazoles as selective nav1.7 inhibitors for pain treatment and method of pain treatment - Google Patents
Substituted isoxazoles as selective nav1.7 inhibitors for pain treatment and method of pain treatmentInfo
- Publication number
- EP4117658A1 EP4117658A1 EP21767873.9A EP21767873A EP4117658A1 EP 4117658 A1 EP4117658 A1 EP 4117658A1 EP 21767873 A EP21767873 A EP 21767873A EP 4117658 A1 EP4117658 A1 EP 4117658A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- navi
- group
- phenyl
- inhibitor
- selectivity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 14
- 208000002193 Pain Diseases 0.000 title description 18
- 150000002545 isoxazoles Chemical class 0.000 title description 13
- 230000036407 pain Effects 0.000 title description 9
- 229940124777 Nav1.7 inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- -1 Tri-substituted isoxazole compounds Chemical class 0.000 claims abstract description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 13
- 239000011734 sodium Substances 0.000 claims abstract description 13
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 13
- 150000001408 amides Chemical class 0.000 claims abstract description 7
- 239000003112 inhibitor Substances 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 150000001924 cycloalkanes Chemical class 0.000 claims description 3
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 230000000155 isotopic effect Effects 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000005323 thioketone group Chemical group 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 238000005556 structure-activity relationship Methods 0.000 abstract description 12
- 238000006467 substitution reaction Methods 0.000 abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- 230000011987 methylation Effects 0.000 abstract description 4
- 238000007069 methylation reaction Methods 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 108091006146 Channels Proteins 0.000 abstract description 2
- 101000694017 Homo sapiens Sodium channel protein type 5 subunit alpha Proteins 0.000 abstract 2
- 102100027198 Sodium channel protein type 5 subunit alpha Human genes 0.000 abstract 2
- 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 abstract 1
- 102100031367 Sodium channel protein type 9 subunit alpha Human genes 0.000 abstract 1
- 208000000094 Chronic Pain Diseases 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000000842 isoxazolyl group Chemical group 0.000 description 6
- 238000007876 drug discovery Methods 0.000 description 5
- 229940005483 opioid analgesics Drugs 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 238000003775 Density Functional Theory Methods 0.000 description 3
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 3
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VSWPGAIWKHPTKX-UHFFFAOYSA-N 1-methyl-10-[2-(4-methyl-1-piperazinyl)-1-oxoethyl]-5H-thieno[3,4-b][1,5]benzodiazepin-4-one Chemical compound C1CN(C)CCN1CC(=O)N1C2=CC=CC=C2NC(=O)C2=CSC(C)=C21 VSWPGAIWKHPTKX-UHFFFAOYSA-N 0.000 description 2
- 238000004057 DFT-B3LYP calculation Methods 0.000 description 2
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- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229950004351 telenzepine Drugs 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 1
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- 208000012488 Opiate Overdose Diseases 0.000 description 1
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- 208000027520 Somatoform disease Diseases 0.000 description 1
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- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
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- 238000009509 drug development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 238000009434 installation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
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- 230000037324 pain perception Effects 0.000 description 1
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- 230000002085 persistent effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
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- 230000001256 tonic effect Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- opioid overdose including both prescription and illicit opioids.
- prescription opioids can be used to treat moderate-to-severe pain and are often prescribed following surgery or injury, or for health conditions such as cancer.
- prescription opioids for the treatment of chronic, non-cancer pain, such as back pain or osteoarthritis, despite serious risks and the lack of evidence about their long-term effectiveness.”
- More than 191 million opioid prescriptions were dispensed to patients in the United States in 2017.
- Opioids are addictive and patients taking them develop tolerance to their pharmacologic benefits, necessitating increased dosages.
- Substituted isoxazoles are potent inhibitors of Navi.7 and their structure-activity relationships have been found tunable for selectivity over Navi .5.
- Structure-activity relationship (SAR) studies demonstrated that subtype selectivity (Navi.7 vs. Navi.5) could be improved with methylation of the amide nitrogen or ortho-substitution on the phenyl ring in the 5-position.
- FIG. 1 illustrates a restricted rotation axis of chirality of telenzepine as is known in the art.
- FIG. 2 illustrates the core structure of the inventive tri-substituted isoxazole compound in accordance with the present disclosure.
- FIG. 3 is a graph of the results from a mouse automated formalin test an isoxazole compound in accordance with the present disclosure.
- FIG. 4 is a density function theory (B3LYP/6-31G) geometry minimization of a simplified methyl ester analog of compound in accordance with the present invention.
- FIG. 5 is a pharmacophore model and SAR on the tri-substituted isoxazole Navi.7 inhibitors in accordance with the present disclosure.
- FIG. 6 is a synthetic pathway for atropisomeric 3, 4, 5 tri-substituted isoxazoles employed for SAR analysis in Navl.7/Navl.5 in vitro assays in accordance with the present disclosure.
- a new class of isoxazole-based Navi.7 inhibitors are disclosed that demonstrate potent inhibition of hNavl.7, tunable selectivity over hNavl.5 and possess ideal starting physiochemical properties for further drug development.
- SAR structure-activity relationship
- a previously unrecognized structural feature in this class of compounds, atropisomerism has been identified.
- the dramatic role that chirality and three-dimensionality plays in influencing biological activity is well established.
- atropisomerism an example of axial chirality, has never been exploited in SAR studies of isoxazole-based small molecules despite their role as a privileged scaffold in medicinal chemistry.
- telenzepine A well-known industrial example of differential activity due to atropisomerism is telenzepine, shown in Fig. 1. Telenzipine is a selective muscarinic antagonist for the treatment of peptic ulcers. The (-)-isomer was eventually found to be 500x less active with much less selectivity than the (+)-isomer at muscarinic receptors in the rat cerebral cortex. Unfortunately, strategies to address atropisomerism in drug discovery are lacking and there are currently no specific guidelines from regulatory agencies on how to handle this time-dependent chirality despite its prevalence and impact on the pharmaceutical industry.
- the present invention exploits the previously unrecognized form of atropisomerism in 3, 4, 5 -tri substituted isoxazoles to yield a new class of Navi .7 inhibitors.
- This provides opportunities for multiple discoveries with respect to the synthetic design of atropisomeric isoxazoles, their characterization and kinetics of chirality, and the subsequent understanding of how this chirality element affects Navi.7 potency and selectivity over Navi.5. More broadly, given the prevalence of substituted isoxazoles in numerous drug discovery programs, which will aid in designing new strategies to recognize and understand the positive or negative impact of atropisomerism across multiple therapeutic programs.
- the 3, 4, 5 -tri substituted isoxazole in accordance with the present invention is based upon general formula I, including a stereoisomer, enantiomer, atropisomer, mixture of enantiomers, mixture of diastereomers, mixture of atropisomers, or isotopic variant thereof; or a pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof:
- R1 is selected from the group of methyl, phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, trifluoromethyl, methoxypehnyl, cyanophenyl, pyridine, furan, and thiophene, and combinations thereof;
- R2 is selected from the group of hydrogen, methyl, trifluoromethyl, halogen, alkynyl, phenyl, amide, methylphenyl, and fluoromethylphenyl, and combinations thereof;
- R3 is selected from the group of hydrogen, keto, thioketo, and combinations thereof;
- R4 is selected from the group of 1-10 carbon branched or straight chain alkyl, hydroxyalky, cyclic, heterocyclic, sulfide, aldehyde, phenyl, and combinations thereof; and
- R5 is selected from the group of hydrogen, methyl, and saturated or unsaturated cycloalkanes having 3-6 carbon atoms.
- Compound 124 includes a meta-substitution on the phenyl ring in the 5-position that results in reversing subtype selectivity.
- Compound 124 was found to be very potent againstNavl .5 (36 nM) as well as Navi.7 (120 nM) again, supporting that subtle structural differences have a profound influence on both potency and selectivity.
- Navi.7 potency was realized when a substitution was introduced at the 4-position of the isoxazole ring as exemplified by the 4-phenyl substitution in compound 106.
- Compound 100 was administered using the mouse automated formalin model at a dosage of 135 mg/kg p.o. Dosage was selected based upon projection from mouse exposure at 5 mg/kg. Early phase and late phase tonic events were measured with a Tmax equal to 15 minutes and a Tl/2 equal to 1.1 hours. Table 2, below, and FIG. 3 summarize the results of the test demonstrating the Navi.7 inhibitory activity of compound 100 relative to vehicle.
- FIG. 5 outlines the synthesis of 3,4,5-trisubstituted isoxazoles in accordance with the present invention.
- Compound 106 was synthesized by this synthetic route using phenyl boronic acid.
- atropisomers around the C-C bond at the 4-position are contemplated with either a single ortho- or meta-substituent.
- Atropisomeric isoxazoles with simple ortho-substitution from aryl boronic acids that includes ortho-fluorine, -chlorine, -bromine, -methyl, and -methoxy may also be made by this synthetic route.
- Chiral separation of tri substituted atropisomeric isoxazoles may be accomplished by interrupting the synthetic route after the Suzuki cross-coupling reaction to yield two complementary methods for separating the atropisomers as shown in FIG. 5.
- the methyl ester offers an ideal site for chiral semi-preparative HPLC separation.
- hydrolysis of the methyl ester to the corresponding carboxylic acid as a handle for separation via classical resolution.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062989186P | 2020-03-13 | 2020-03-13 | |
PCT/US2021/022187 WO2021183937A1 (en) | 2020-03-13 | 2021-03-12 | Substituted isoxazoles as selective nav1.7 inhibitors for pain treatment and method of pain treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
EP4117658A1 true EP4117658A1 (en) | 2023-01-18 |
EP4117658A4 EP4117658A4 (en) | 2024-05-15 |
Family
ID=77670919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21767873.9A Pending EP4117658A4 (en) | 2020-03-13 | 2021-03-12 | Substituted isoxazoles as selective nav1.7 inhibitors for pain treatment and method of pain treatment |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP4117658A4 (en) |
KR (1) | KR20220166810A (en) |
WO (1) | WO2021183937A1 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418667B1 (en) * | 1989-09-22 | 1995-08-16 | BASF Aktiengesellschaft | Carboxylic acid amides |
EP2306837B2 (en) * | 2008-07-09 | 2023-10-25 | Basf Se | Pesticidal active mixtures comprising isoxazoline compounds i |
EP3193610A4 (en) * | 2014-09-09 | 2018-04-04 | Chromocell Corporation | Selective nav1.7 inhibitors for the treatment of diabetes |
WO2017133931A1 (en) * | 2016-02-04 | 2017-08-10 | Nestec S.A. | In vitro production of pancreatic beta cells |
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2021
- 2021-03-12 WO PCT/US2021/022187 patent/WO2021183937A1/en unknown
- 2021-03-12 EP EP21767873.9A patent/EP4117658A4/en active Pending
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WO2021183937A1 (en) | 2021-09-16 |
KR20220166810A (en) | 2022-12-19 |
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